19-nor-progesterone



United States Patet 3,89,88ll Patented May 14, 1963 ice 3,089,880 B-NOR-PRUGESTERONE Josef Fried, Princeton, and Mariano A. Guitlucci, Edison, N.J., assignors to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Filed Aug. 4, 1961, Ser. No. 129,235 7 Claims. (Cl. 260-3973) This invention relates to, and has for its objects the provisions of new physiologically active steroids, methods for preparing the same, and intermediates useful in such preparations.

The final products the general formulae of this invention include steroids of wherein R is in either the alpha or beta position and represents hydrogen or lower alkyl (preferably methyl). These compounds are physiologically-active substances which possess progestational activity and hence can be used in lieu of known progestational agents, such as progesterone, in the treatment of habitual abortion. For this purpose,

they can be administered in the same manner as proges-' terone, for example, the dosage being adjusted for the relative potency of the particular steroid.

The compounds of this invention can be prepared by reducing a compound of the formula wherein R is as hereinbefore defined and R is lower alkyl by treatment with lithium and liquid ammonia. Suitable starting materials include the l6et,17cn-8.C6l0l1id5 of 3- (lower alkoxy)-l9-nor-l,3,5(10)-pregnatriene-16a,l7a-diol- 20-ones (e.g., 3-methoxy-19-nor-l,3,5(l0)-pregnatriene- 16a,l7a-dio1-20-one) and 3-(lower alkoXy)-6-(-lower alkyD- l9-nor-1,3,5(10)-pregnatr1ene 16a,17a diol-20-ones (e.g.,

3-methoxy 6a methyl-l9-nor-l,3,5(10) pregnatriene- 16,17a-diol-20-0ne and 3-methoXy-6 8-methyl-l9-nor-1,3, 5(lO)-pregnatriene-16a,17a-diol-20-one). These starting steroids can be prepared by the method described in our application, Serial No. 129,233, filed on even date herewith.

The reaction yields new intermediates of this invention of the formula t OH-CH wherein R and R are as hereinbefore defined.

These enols are then hydrolyzed. The nature of the product formed will depend on the conditions of the hydrolysis. Thus, if a mineral acid (e.g., dilute sulfuric acid and dilute hydrochloric acid) is used as the hydrolyzing agent, a 4-pregnene of the following formula is formed:

wherein R is as hereinbefore defined.

If, however, the hydrolysis is carried out by use or an organic carboxylic acid (e.g., oxalic acid), then a 5(l0)- pregnene of the following formula is formed:

wherein R is as hereinbefore defined.

The resulting 16,20-dihydroxy compounds are then oxidized, as by treatment with a hexavalent chromium compound -(e.g., chromic oxide) to yield the final 16,20-diketo compounds of this invention.

The following examples illustrate the invention (all temperatures being in 'centigrade):

EXAMPLE 1 19-N0r-3-Meth0xy-2,5 (10) -Pregnadiene-16a,20fi-Diol A solution of mg. of 3-methoxy-19-nor-1,3,5(10)- pregnatriene 16oc,17ot diol-ZO-one 16a,17oc-acetonide in 35 ml. of dry ether is added to 50' ml. of liquid ammonia followed by 100 mg. of lithium wire in small portions. After stirring for 40 minutes, while immersed in a Dry Ice-acetone bath, 5 ml. of methanol is added, which is followed by an additional 400 mg. of lithium wire. The resulting reaction mixture is stirred until all the ammonia has evaporated, following which water is added and the mixture is extracted with ether. The combined ether extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness in vacuo. Crystallization of the crude product from acetonehexane yields about 72 mg. of 3-metl1oxy-19-nor-2,5(10)- pregnadiene-l6a,20 3-diol of the followin g properties: M.P. about l78l79; [u] +97 (c. .94 in chlf.);

EXAMPLE 2 Following the procedure of Example 1 but substituting an equivalent amount of 6a-methyl-3-methoxy-l9-norl,3,5(l) pregnatriene l6a,l7a-diol20-one 16ot,l7aacetonide for the acetonide, 6a-methyl-l9-nor-3-methoxy- 2,5(10)-pregnadiene-l6a,20;8-diol is obtained.

EXAMPLE 3 Following the procedure of Example 1 but substituting an equivalent amount of 6/3-methyl-3-methoxy-l9-nor-l,3, l0) -pregnatriene-l6e, l7a-diol-20-one 160:,17oc-3C6t0nid for the acetonide, 6B-methyl-l9-nor-3-methoxy-2,5(l0)- pregnadiene-IMJOfl-diol is obtained.

EXAMPLE 4 19-N0r-4-Pregnene-I6a,20 3-Di0l-3-One Analysis.Oalcd. for C20H3003 C, H, 9.50. Found: C, 75.89; H, 9.40.

EXAMPLE 5 6 Ot-M eth yI-l 9-N 0r-4 -Pregnene-1 6 ,2 Ofl-Diol-S-One Following the procedure of Example 4 but substituting an equivalent amount of 6u-methyl-3-methoxy-19-nor- 2,5 l0)-pregnadiene-l6a,20/3-diol for the steroid reactant, 6a methyl-19-nor-4-pregner1e-l6a,20fl-diol-3-one is obtained.

EXAMPLE 6 6B-Methyl-1 9-Nor-4-Pregnene-16u-20B-Di0l-3-One Following the procedure of Example 4 but substituting an equivalent amount of 6fl-methyl-3-methoxy-l9-nor- 2,5 l0)-pregnadiene-l6a-20B-diol for the steroid reactant, 6/3 methyl-19-nor-4-pregnene-l6e,20fl-diol-3-one is obtained.

EXAMPLE 7 1 9-N0r-5 (10) -Pregnene-16a,20/3-Di0l-3-One To a solution of 16 mg. of 3-methoxy-l9-nor-2,5(10)- pregnadiene-l6u-20fi-diol in 1.25 ml. of methanol is added 0.9 ml. of a solution containing 230 mg. of oxalic acid in 3 ml. of water. The reaction mixture is stirred at room temperature, poured into ice-water, and extracted with chloroform. The combined chloroform extracts are washed with sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness in vacuo.

EXAMPLE 8 6a-Mezlzyl-19-N0r-5 (10) -Pregnene-16a-20/3-DioI-3-One Following the procedure of Example 7 but Substituting an equivalent amount of 6u-methyl-3-metl1oxy-19-nor- 2,5'( l0)-pregnadiene-l6a,20/3-diol for the steroid reactant, 6a methyl l9-nor-5(l0)-pregnene-l6a,20fi-diol-3-one is obtained.

EXAMPLE 9 6fi-Methyl-19-Nor-5 (10)-Pregnene-1 641,2 0,8-Diol- 3-0ne Following the procedure of Example 7 but substituting an equivalent amount of 6B-methyl-3-methoxy-19-nor- 2,5( l0)-pregnadiene-l6a,20;9-diol for the steroid reactant, 65 methyl l9-nor-5(l0)-pregnenc-l6a,20/3-diol-3-one is obtained.

EXAMPLE l0 19-N0r-16-Ketdprogesterone To a solution of 10 mg. of l9-nor-4 pregnene-l6a,20,8- diol-3-one in 2 ml. of acetone is added dropwise 0.30 ml. of chromic acid-sulfuric acid reagent containing 20 mg. of CrO and 32 mg. of H 50 in 1 ml. of aqueous acetone. The reagent is consumed rapidly and after stirring for a total of 15 minutes methanol is added to reduce the excess chromic acid. Water is added and the mixture extracted with chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residual 19-nor-16-ketoprogesterone gives a strong positive ferric chloride test.

EXAMPLE 1 l 6a-Methyl-19-N0r-l 6-Ket0progester0ne Following the procedure of Example 10 but substituting an equivalent amount of fiat-methyl-l9-nor-4-pregnenel6a,20,B-diol-3-one for the steroid reactant, 6a-methyl-19- nor-l6-ketoprogesterone is obtained.

EXAMPLE l2 6p-Methyl-19-N0r-1 6-K eloprogesterone Following the procedure of Example 10 but substituting an equivalent amount of 6/3methyl-l9-nor-4-pregnene-l6a,20fi-diol-3-one for the steroid reactant, 6,8- methyl-l9-nor-l6aketoprogesterone is obtained.

EXAMPLE l3 19-Nor-5 (1 0 -Pregncne-3,1 6,20-Trione Following the procedure of Example 10 but substituting an equivalent amount of l9-nor-5(10)-pregnene-- 16a,20B-diol3-one for the steroid reactant, 19-nor-5(l0)- pregnene-3,l6,20-trione is obtained.

EXAMPLE l4 6a-Methyl-19-N0r-5 (1 0) -Pregncue-3,16,20-Tri0ne Following the procedure of Example 10 but substituting an equivalent amount of 6a-methyl-l9-nor-5 10)- preguene-l6a-20fl-diol-3-one for the steroid reactant, 6ozrnethyl-l 9-n0r-5 10)-pregnene-3,16,20-trione is obtained,

EXAMPLE 1 5 6/9-Methyl-J9-No1-5(1 0 -Pregnene-3,16,20-Tri0ne Following the procedure of Example 10 but substituting an equivalent amount of 6;8-methyl-19-nor-5(l0)- pregnene-l6a,20;9-diol-3-one for the steroid reactant, 6/3- methyl-l9-nor-5( l0) -pregnene-3, 16,20-trione is obtained.

This invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

l. A compound selected from the group consisting of 6 (lower alkyl l9 nor-l6-ketoprogesterone, l9-nor-5 10) -pregnene-3,16,20-trione and 6- (lower alkyl) -l9-nor- 5 10) pregnene-3, 16,20-trione.

2. a-rnethyl-19-nor-16-ketop rogesterone.

3. 6,8methyl-l9-nor-l6-ketoprogesterone.

4. A compound selected from the group consisting of 19 nor 3-(lower a1koxy)-2,5(10)-pregnadiene-l6a,20[- diol and 6-(lower alkyl)-l9-nor-3-(lower alkoxy)-2,5 l) -pregnadiene-160:,20B-di0l.

5. 19 nor 3 methoxy-2,5(10)-pregnadiene-16a,20fldiol.

6. A compound selected from the group consisting of 6-(lower'a1ky1)-l9-nor-4-megnene46a,20,B-d-iol-3-one, 19 nor 5 pregnene-16a,20/S'-diol-3-one and 6-(lower ialky-l) -19-nor-5 10) -pregnene-16a,20fi-diol-3-one.

"i. A process for preparing a compound selected from the group consisting of 19-nor-3-(lower 'alkoxy)-2,5(10)- pregnadiene-l6a,20;3-diol and 6-(lower \a1kyl)-19-noI-3- (lower alkoxy)-2,5 ('10)pregnadiene-16a,20;8-dioi, which comprises treating a corresponding compound selected from the group consisting of l9-n0r-3-(lower alkoxy)-l,3, 5( 10) pregnatriene :,171x-di0l-20-0Il6 '1 6a,17a-acetonide and 6-(lower alky1)-l9-nor-3(lower alkoxy)-1,3, 5(10) pregnatriene l6u,l7a-diol-20'-one 16a,17a-acet0- nide with lithium and liquid ammonia.

References Cited in the file of this patent UNITED STATES PATENTS 2,799,690 Fried et al July 16, 1957 OTHER REFERENCES Fiegser et 211.: Steroids (1959), Reinhold Pub. Corp. p. 58 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 6-(LOWER ALKYL-19-NOR-16-KETOPROGESTERONE, 19-NOR(10)-PREGNENE-3,16,20-TRIONE AND 6-(LOWER ALKYL)-19-NOR5(10)-PREGNENE-3,16,20-TRIONE. 